Combinatorial analysis of tumorigenic microRNAs driving prostate cancer.

摘要

Prostate cancer is the leading non-cutaneous malignancy affecting men in the United States. One in every six men will be affected by prostate cancer. Due to the high incidence of prostate cancer, there is a need to develop biomarkers capable of identifying tumors from benign prostatic lesions. miRNAs are small molecules that regulate protein translation and impact cellular integrity when dysregulated. It is widely thought that miRNAs have the potential to serve as biomarkers.;This study utilizes a unique combinatorial analysis of miRNA dysregulation to identify key miRNAs involved in prostate tumor initiation, progression and metastasis. Numerous dysregulated miRNAs potentially influence cancer development. A unique bioinformatically driven, network based approach was used to rank potential miRNAs that drive tumor progression. This study showed that miRNAs preferentially regulate highly connected proteins and transcription factors that affect numerous downstream targets. Thus dysregulation of a single highly connected miRNA could severely impact homeostatic maintenance of the tissue.;In combination with miRNA profiling of a cancer cell progression model, the utilization of laser captured microdissection was used to separate cancer specific microRNA portraits from background differences arising from stroma cells, lymphocytes, and remaining normal epithelial cells. Integration of miRNA profiles with information gathered using networks biology and targeted proteomics resulted in the identification of a key miRNA that affects prostate cancer development and may be useful as a novel biomarker for identification/ staging of prostate cancer.;Human miR-125b was identified as a potential miRNA suppressor of tumor formation. Previous work has identified miR-125-b as the post-transcriptional regulator of the ErbB2/ ErbB3 growth factor receptor family. Loss of miR-125b drives up expression of ErbB2/ ErbB3 activating downstream PI3K/AKT and RAS oncogene pathways. The level of miR-125b decreases 3-5-fold between benign and tumor epithelium. Further, miR-125b decreases during the development of prostatic intraepithelial neoplasia, which is regarded as an early indicator of prostate cancer. Thus miR-125b may be an ideal marker of early changes indicative of cancer. Restoration of miR-125b into highly tumorigenic, metastatic cells reduces mobility and invasion of underlying tissues. Taken together these data show miR-125b is a tumor suppressor in the healthy prostate.